Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q99542 (matrix metalloproteinase)
 15,999 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The therapeutic antitumor effect of clarithromycin (CAM) was examined with the 13762NF mammary adenocarcinoma and F-344 rat system. When CAM treatment at a dosage of 2 mg/kg of body weight orally for 21 days was commenced after inoculation of the tumor, no significant decrease in death rate was observed, although the loss in body weight was less than that in the untreated group. When tumor-bearing (TB) rats were treated with CAM in combination with carboplatin or cyclophosphamide, a significant decrease in the death rate was obtained, although neither treatment alone proved to be effective. A beneficial effect was also observed when CAM treatment was combined with surgical treatment. CAM showed no direct cytotoxicity to this tumor in vitro according to the MTT (3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. Spleen cells obtained from TB rats receiving CAM treatment showed a stronger tumor-neutralizing activity than those from rats which had not received CAM treatment (Winn assay). Enhanced induction of cytotoxic cells to allogeneic tumor was also observed in rats immunized with allogeneic tumor cells together with CAM treatment (51Cr release assay). The 13762NF tumor produces transforming growth factor-beta (TGF-beta), tumor necrosis factor alpha, and matrix metalloproteinase-9, and treatment of tumor cells with CAM in vitro for 24 h significantly inhibited the expression of the genes coding for these proteins (reverse transcription-PCR). Levels of expression of the TGF-beta and interleukin-6 genes of spleen cells obtained from CAM-treated TB rats were both significantly lower than those of spleen cells from CAM-untreated TB rats. This study suggests that CAM has biological response modifier activities resulting in a beneficial therapeutic antitumor effect and might be useful for the treatment of human cancers.
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PMID:Therapeutic effect of clarithromycin on a transplanted tumor in rats. 986 67

Collagen gels in vitro can be contracted by fibroblasts. The role of matrix metalloproteinases (MMPs) in the contraction of collagen lattices by human neonatal foreskin fibroblasts (HuFFs) was investigated in tissue culture media supplemented by various doses of known gelatinase inhibitors. Fluorescent assays with model gelatinase substrates and media conditioned by fibroblasts apparently confirmed the ability of chemically modified tetracyclines (CMTs) to act as inhibitors of MMP2, and zymography demonstrated that this was the major cell-derived MMP activity. There were no observable effects on the rate of contraction of attached FPCLs containing 6 x 10(4) HuFFs (passages 18-25) with either CMT-5 or CMT-2 at all concentrations tested (0-100 micrograms/mL). However, at greater than 20 micrograms/mL doxycycline and greater than 5 micrograms/mL CMT-3, FPCL contraction was completely abolished. Quantitative assessment of cell viability by means of the MTT assay in monolayer and qualitatively within the FPCLs with CalceinAM suggested that differences were not due to cytotoxic effects. Seeding FPCLs with lower-passage fibroblasts produced identical trends. These results may implicate the involvement of MMPs in the process of gel contraction, although tetracyclines have effects additional to their ability to inhibit MMPs directly.
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PMID:Tetracycline-based MMP inhibitors can prevent fibroblast-mediated collagen gel contraction in vitro. 997 28

The antitumor activity of cinnamamide (CNM), an agent acting on matrix metalloproteinase (MMP), was investigated in the present study. CNM displayed low cytotoxicity. By the MTT assay the IC50 (50% inhibitory concentration) values of CNM on cell proliferation ranged from 1.29 to 1.94 mM in human oral epidermoid carcinoma KB cells, human hepatoma BEL-7402 cells and human fibrosarcoma HT-1080 cells. Moreover, the IC50 for human fetal lung 2BS cells reached 4.33 mM. The administration of CNM in the range of 50-150 mg/kg (i.p. or p.o.) showed moderate antitumor effects in mice. When administered i.p. or p.o., CNM (150 mg/kg) inhibited the growth of transplanted hepatoma 22 by 48.8 or 40.5%, respectively. At the dose of 100 mg/kg, CNM inhibited the growth of colon 26 carcinoma by 39.0% and that of Lewis lung carcinoma by 53.9%. In the Lewis lung carcinoma model, CNM at the dose of 100 mg/kg (i.p.) also reduced the lung metastasis by 59.1%. Gelatine zymography revealed that CNM was able to decrease the level of MMP-2 in conditioned medium of HT-1080 tumor cells in a concentration-dependent manner. These results indicate that CNM is an antitumor agent with low cytotoxicity acting on MMP and may serve as a lead compound in the development of antitumor drugs.
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PMID:Cinnamamide, an antitumor agent with low cytotoxicity acting on matrix metalloproteinase. 1075 63

We have previously reported that invasiveness of mouse glioma G-26, which expresses CD44 adhesion molecule, was inhibited in vitro following treatment with anti-CD44 antibody or mouse interferon alpha/beta (MuIFN alpha/beta). Here, we evaluated whether the expression of transmembrane CD44 adhesion molecule and/or secretion of extracellular matrix metalloproteinases (MMPs) were affected when glioma cell invasion was inhibited. Flow cytometric evaluation of CD44 adhesion molecule expression in G-26 glioma using anti-CD44 antibody, confirmed that G-26 cells were CD44+. Following 3-day treatment with MuIFN alpha/beta at 8 x 10(2) or 8 x 10(3) IU/ml of glioma cells, the expression of CD44 was not significantly affected as reflected by CD44+ cell number and fluorescence intensity. The pretreatment of glioma cells for 1 day with anti-CD44 antibody resulted in a 30-60% decrease of CD44 expression. This coincided with significantly (p < 0.05) lower cell activity as judged by MTT assay for mitochondrial activity. The zymographic evaluation of MMP activity in the G-26 glioma cell culture showed a high level of the active form of MMP-2. This level of MMP-2 was decreased following 3 day treatment of G-26 glioma cells with either 8 x 10(2) or 8 x 10(3) IU/ml of MuIFN alpha/beta but only the latter concentration produced statistically significant 55% decrease. However, following a 1 day treatment of G-26 glioma cells with anti-CD44 antibody, the level of active MMP-2 form was not significantly affected. These findings indicate that while the inhibitory effect of IFN on glioma invasion was accompanied by a decreased level of the active form of MMP-2 released extracellularly, the expression of the transmembrane CD44 adhesion molecule was not affected. Conversely, anti-CD44 antibody pretreatment of G-26 glioma, which led to the inhibition of glioma invasion, resulted in decreased CD44 expression and lower cell activity but had no effect on the MMP-2.
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PMID:CD44 expression and MMP-2 secretion by mouse glioma cells: effect of interferon and anti-CD44 antibody. 1120 62

Docetaxel is a chemical compound belonging to the taxoid class of anticancer agents. Batimastat (BB-94) is the first matrix metalloproteinase inhibitor entering clinical trials. To improve the treatment of tumors, we studied the combined effects of docetaxel and batimastat on mouse forestomach carcinoma (MFC), and compared them with doxorubicin. In vitro growth curve analysis, MTT assay, and clonogenic assay were used to determine the cytotoxic effect of docetaxel or/and BB-94 on MFC. They showed that docetaxel, but not BB-94, had a significant cytotoxicity and that the effect of docetaxel was not enhanced by BB-94. In an early stage MFC tumor model, an obvious antitumor effect of docetaxel or doxorubicin given iv at maximum tolerated dose (MTD) was observed. Tumor growth inhibition was greater for docetaxel + BB-94 (96.0%) than for doxorubicin + BB-94 (88.0%), docetaxel (89.0%), doxorubicin (68.0%), and BB-94 (33.0%). Docetaxel showed activity against advanced stage MFC tumor in a dose-dependent manner and was more effective at MTD than doxorubicin, with 4/5 regression, 46.5 days tumor growth delay, and 2.8 log10 tumor-cell kill. Our results suggest that docetaxel is an effective new cytotoxic drug against MFC tumor and that BB-94 enhances the antitumor activity of docetaxel in the dose and schedule used.
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PMID:Potentiation of docetaxel antitumor activity by batimastat against mouse forestomach carcinoma. 1121 20

We have previously reported on the anti-invasive and angiosuppressive effects of SI-27, an anti-matrix metalloproteinase (MMP) agent. The molecular mechanism of its anti-MMP action, however, has not yet been determined. The purpose of this study was to investigate the effects of SI-27 on MMP- 1, -2, -3, -9, and TIMP-1, -2 secreted by human glioma cell lines (U87MG, U251MG, U373MG, and Y98G). When cells were exposed to non-cytotoxic concentrations of SI-27 (preliminarily determined by the MTT assay), expressions of mRNAs for the enzymes was not inhibited. For an MMP activity assay, we employed the fact that active MMPs could cleave modified pro-urokinase to form active urokinase, which then acted on S-2444 peptide to create a chromogenic product. Secretion of all pro-MMPs from glioma cells was not significantly reduced by SI-27. However, activation of pro-MMPs was significantly inhibited in a dose-dependent manner ((IC50 values for MMP-2; U87MG, 3.5 microg/ml; U25 IMG, 4.2 microg/ml; U373MG, 4.8 microg/ml; Y98G, 4.0 degreesg/ml); (IC50 values for MMP-9; 251MG, 7.2 microg/ml, U373MG, 2.8 microg/ml). In addition, active MMPs were not inhibited by SI-27. These findings were supported by zymographic analysis and by collagenolysis assay data. TIMP-1 and -2 were also not inactivated by SI-27. These findings suggest that SI-27 targets the activation process of pro-MMP. S-2444, a specific chromogenic peptide, was useful for quantitative analysis of the activity of MMP subtypes in this study.
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PMID:Suppression of matrix metalloproteinase activity by SI-27: detection by a new activity assay with S-2444, a specific chromogenic peptide. 1216 Jan 35

The role of vascular endothelial growth factor (VEGF) during peritoneal dissemination of ovarian carcinoma and the association with tumor microvessel density (MVD) and matrix metalloproteinase (MMP) activity was investigated. To this end, MVD, tumor tissue and ascitic fluid levels of VEGF, and MMP activity of ascitic fluid were examined in patients with ovarian cancer and benign ovarian tumor. The effect of ascites on cell growth, cell invasion activity and angiogenesis was investigated in vitro. Ascitic fluid and tumor tissue samples were obtained from 15 patients with benign ovarian tumor and 24 patients with ovarian carcinoma. Tissue extract and ascitic fluid levels of VEGF were measured using enzyme immunoassay. Tumor microvessels were detected immunohistochemically. MMP activity was measured by gelatin zymography. For the in vitro experiment, the SKOV-3 human ovarian carcinoma cell line was utilized. Cell growth was examined using MTT-assay, cell invasion activity was measured by Matrigel in vitro invasion assay, and neovascularization was assessed using an angiogenesis kit. VEGF levels in tissue extract and ascitic fluid, MVD, expression of active form MMP-2 in ascitic fluid and ascites volume were higher in ovarian cancer patients than in benign ovarian tumor patients. In addition, these were elevated in stage III and IV diseases compared to stage I and II diseases in ovarian cancer patients. MVD and expression of active form MMP-2 in ascitic fluid were closely correlated with VEGF level in tissue extracts, and MVD and ascites volume were closely correlated with VEGF level in ascitic fluid. Cell invasive activity and angiogenesis activity increased when cells were exposed to ascites. These increases were apparent when exposed to ascites obtained from ovarian cancer patients and were related to VEGF concentrations of ascitic fluid and expression of active form MMP-2 in ascitic fluid. The increased VEGF secreted from tumor cells is suggested to enhance tumor growth through angiogenesis, to produce ascites and to elevate ascitic VEGF concentrations and expression of active form MMP-2. The progression of peritoneal involvement may be induced by elevated VEGF and expression of active form MMP-2, followed by increased VEGF in the primary tumor. Control of VEGF in the primary tumor may become an effective strategy against peritoneal dissemination of ovarian carcinoma.
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PMID:Vascular endothelial growth factor activating matrix metalloproteinase in ascitic fluid during peritoneal dissemination of ovarian cancer. 1246 50

The matrix metalloproteinases (MMPs) are likely to contribute to tumor cell invasion, metastasis and angiogenesis. Several MMP inhibitors have been developed, recently and their anti-tumor efficacy is being evaluated in clinical trials. FYK-1388 is a novel broad MMP inhibitor which blocks the activity of MMP-1, -2, -3, -7, -9, -13 and -14 (MT-MMP-1). It is especially effective against MMP-2 and -9 more so than other MMP inhibitors such as Marimastat, Ro 32-3555 and D-2163. Here, we investigated the anti-tumor efficacy of FYK-1388 using the human fibrosarcoma cell line HT-1080. These cells produced MMP-2 and -9, which FYK-1388 inhibited at a dose of 10(-8) M. FYK-1388 at 0.2 mg/mouse/day significantly suppressed tumor growth when given by s.c. injection for 22 days, experimental lung metastasis after 5 days s.c. injection and also suppressed tumor-induced angiogenesis in the dorsal air sac assay after 7 days s.c. injection. In the MTT assay, FYK-1388 had no effect on the in vitro growth of HT-1080 cells. These results suggest that FYK-1388 possesses anti-tumor efficacy as a result of inhibiting angiogenesis through the suppression of MMP-2 and -9 activity.
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PMID:A novel matrix metalloproteinase inhibitor, FYK-1388 suppresses tumor growth, metastasis and angiogenesis by human fibrosarcoma cell line. 1252 23

We have elucidated the pharmacological action of the anti-matrix metalloproteinase inhibitor BE16627B on glioma cells. The study was limited to the noncytotoxic dose range. The aim of the study was to investigate whether the cytotoxicity of BE16627B, an anti-MMP agent, is related to apoptosis in the human malignant glioma cell lines U87MG, U251MG, and U373MG. MTT assay was performed to detect the cytotoxic dose range. Agarose gel electrophoresis was performed with purified genomic DNA following exposure to 20 to 500 microM BE16627B for 24 h, compared with 0 microM for the control group. Transmission electron microscopy (TEM) was employed to study nuclear fragmentation following exposure to 0, 20, and 500 microM of the agent for 24 h. An in situ endolabeling assay was performed to determine the index of apoptotic induction. MTT assay revealed that concentrations of 100 microM and above were cytotoxic. DNA laddering was demonstrated in agarose gel electrophoresis. TEM disclosed condensing and fragmentation of the chromatin. None of these changes were observed in the control group and the noncytotoxic dose group. The in situ endolabeling study disclosed that the apoptotic index was significantly elevated by cytotoxic doses of this agent (U373MG; control, 4.0%; 500 microM, 68.5%). These results indicated that cytotoxic concentrations of BE16627B induced apoptosis in human malignant glioma cell lines. In our previous report, this agent inhibited activity of MMP in noncytotoxic concentrations. Further study should be done to determine the pharmacological action of toxic BE16627B.
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PMID:Apoptotic induction by BE16627B on human malignant glioma cell lines by an anti-matrix metalloproteinase agent. 1460 27

When we previously examined the participation of local expression of interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNFalpha) in wound healing of an intestinal anastomosis under septic conditions in mice, we found that IL-10 and TNFalpha expressions were markedly enhanced around the anastomosis and that wound healing was impaired in this animal model. The purpose of the present study was to investigate the combined effect of IL-10 on proliferation and remodeling of the extracellular matrix (ECM) of cultured human skin fibroblasts. Human skin fibroblasts were cultured for 48 h with IL-10 and/or TNFalpha at various concentrations, then the proliferation rates were determined using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The concentration of transforming growth factor-beta1 (TGFbeta1) in cell culture supernatants was measured by enzyme-linked immunosorbent assay, and type I collagen protein and matrix metalloproteinase-I (MMP-I) were detected by indirect immunofluorescence in cultured cells incubated for 48 h with 10 ng/ml of IL-10 and/or 10 ng/ml of TNFalpha. IL-10 itself had no effect on fibroblast proliferation, but reduced TNFalpha-induced fibroblast proliferation. The concentration of TGFbeta1 in cell culture supernatants was significantly lower in the presence of TNFalpha and IL-10 than in the presence of TNFalpha alone. Immunolabeling of fibroblasts for type I collagen protein was decreased in cells incubated with IL-10 and/or TNFalpha compared to controls. MMP-I immunolabeling was increased in cells incubated with IL-10, IL-10 and TNFalpha compared to control and cells incubated with TNFalpha. It is suggested that IL-10 is an inhibitory factor for the remodeling of the ECM during wound healing.
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PMID:Interleukin-10 suppresses proliferation and remodeling of extracellular matrix of cultured human skin fibroblasts. 1473 Feb 22


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